Interleukin-2 is a cytokine that was originally described as permitting the activation and proliferation of T lymphocytes. It has been used clinically for the stimulation of effector immune response in certain cancers and infectious disease. Interleukin-2 was approved under the tradename Proleukin® in 1998 for the treatment of metastatic renal cell carcinoma. The posology of Proleukin® includes the intermittent administration of high dosage of IL-2, typically 42.106 UI per 8 h for a patient of 70 kg by continuous infusion or by daily subcutaneous injection for 5 days, which can be repeated several times after a free-treatment period.
Recently, it was shown that interleukin-2 is essential for the survival and activation of Tregs. At doses 10 to 100 times lower than Proleukin®, IL-2 does not stimulate immunity but restores self-tolerance by specifically activating cells that regulate immunity, regulatory T cells (Treg). IL-2 therefore exerts selective biological effect on the Treg/Teff balance, a key immunological driver of immune homeostasis. Such a property paves the way for the use IL2 in the treatment of autoimmune diseases and inflammatory disorders (AIDs) inherently due to a Treg insufficiency (Klatzmann & Abbas, Nature Reviews Immunology, 2015, 15, 283-294). IL-2 is currently being investigated at low dose in the treatment of several autoimmune and inflammatory diseases such as type-1 diabetes.
Interleukin-2 is susceptible to degradation in the presence of water and oxygen. According to the prior art, Interleukin-2 may undergo chemical degradation and physical instability in solution. Accordingly, the development of lyophilized formulations was initiated to avoid such degradation reactions. In that respect, several studies were performed in order to identify stabilizers to improve the stability of IL-2 in lyophilized formulation. For instance, Hora et al. (Develop. Biol. Standard, 1991, vol 74, 295-306) describe the use of amorphous excipients such as amino-acids, non-ionic surfactant, hydroxypropyl-β-cyclodextrin or serum albumin as lyophilization stabilizers for formulating interleukin-2. In order to produce stable standards of cytokines such as Il-2, the World Health Organization (WHO) recommends freeze-drying the protein in the presence of appropriate excipient and buffer agent and to store the resulting formulation in dry condition, at low temperature, and under inert atmosphere (Mire-Sluis at al., Journal of immunological methods, 1998, 216, 103-116). Noteworthy, Proleukin®, for the treatment metastatic renal cell carcinoma, is marketed as a lyophilized composition comprising interleukin-2, mannitol, sodium dodecyl sulphate and sodium dihydrogen phosphate dihydrate, which is packaged in vial under inert condition and must be stored at 2° C. to 8° C. Mannitol is present as a lyophilization stabilizer. Proleukin® is to be reconstituted with water for injection. Once reconstituted, Proleukin® should be used immediately and, in any case, within 24 h after reconstitution (see for instance the Summary of Product Characteristics for Proleukin® in United Kingdom, Jan. 20, 2015, Novartis Pharmaceuticals UK Ltd).
Such lyophilized formulations are not appropriate for self-administration and long-term treatments because the formulations have to be reconstituted and can only be stored upon short period of time once reconstituted.
There is thus a need for alternative pharmaceutical compositions of interleukin-2.